Intergenerational effects of dietary restriction on insulin/IGF signaling and reproductive development

Abstract The roundworm C. elegans transiently arrests larval development to survive extended starvation ( 1 ), but such early-life starvation reduces reproductive success ( 2, 3 ). Maternal dietary restriction (DR) buffers progeny from starvation, increasing reproductive success ( 4 ). It is unknown why early-life starvation decreases reproductive success and how maternal diet modifies this process. We show here that extended starvation in first-stage (L1) larvae followed by unrestricted feeding results in a variety of abnormalities in the reproductive system, including glp-1/ Notch-sensitive germ-cell tumors and uterine masses that express neuronal and epidermal markers. We found that maternal DR reduces the penetrance of starvation-induced abnormalities, including tumors. Furthermore, we show that maternal DR reduces insulin/IGF signaling (IIS) in progeny, and that daf-16 /FoxO and skn-1 /Nrf, transcriptional effectors of IIS, are required in progeny for maternal DR to suppress abnormalities. daf-16 /FoxO activity in somatic tissues is sufficient to suppress starvation-induced abnormalities, suggesting cell-nonautonomous regulation of reproductive system development. This work reveals complex inter- and intra-generational effects of nutrient availability mediated by IIS with consequences on developmental integrity and reproductive success. One Sentence Summary Intergenerational effects of diet on IIS